S-(4-biphenyl)-thiosulphuric acids and their salts, method for producing the same and method for producing 4-mercaptobiphenyls

ABSTRACT

The invention relates to novel S-(4-biphenyl)-thiosulfuric acids and their salts, to a method for producing them from S-(4-biphenyl)-thiosulfinic acids and their salts, and to a method for producing 4-mercaptobiphenyls from the S-(4-biphenyl)-thiosulfuric acids and their salts.

This application is the national phase and PCT/EP98/06453 filed Oct. 12,1998 now WO99/20604.

BACKGROUND OF THE INVENTION

The present invention relates to novel S-(4-biphenyl)-thiosulphuricacids and salts thereof, to a process for their preparation startingfrom S-(4-biphenyl)-sulphinic acids and salts thereof and thepreparation of 4-mercaptobiphenyls from the S-(4-biphenyl)-thiosulphuricacids and their salts.

4-Mercaptobiphenyls are important intermediates for preparingpharmaceutically and agiochemilcally active compounds (see, for example,BE-A 887 423, U.S. Pat. No. 3,912,757 and WO 96/25 936). Some processesfor preparing 4-mercaptobiphenyls are already known; however, all ofthem are unsatisfactory.

Thus, biphenylsulphonyl chloride can be reduced using amalgamated zinc,metallic tin or tin(II) chloride (see, for example, J.A.C.S. 66, 1674(1944), Chem. Ber. 13, 386 (1880) and Ann. Univ. Marie Curie-Sklodowska,Section Aa, Volume Date 1966 No. 21, 65 to 83 (1967)). In all of theseprocesses, waste waters containing heavy metal salts are produced, thedisposal of which involves great costs.

It is also possible to diazotize 4-aminodiphenyl, followed by reactionwith potassium ethyl xanthate and hydrolysis of the resulting thioester(see DE-A 23 17 142, pp. 34 to 35). Here, water-soluble nickel chloridehas to be employed which likewise passes into the waste water, where thedisposal involves high costs.

The reaction of p-hydroxybiphenyl with dimethylthiocarbamoyl chloridefollowed by Newman-Kwart rearrangement and finally hydrolysis (see J.Het. Chem. 15, 281 (1978) and WO 96/25 936) affords 4-mercaptobiphenylonly in a yield of 39%.

When 4-bromobiphenyl is reacted with sodium methyl sulphide or sodiumethyl sulphide and the resulting thioether is cleaved, good yields of4-mercaptobiphenyl (for example 96% of theory) are only obtained whenhandling of the carcinogenic hexamethylphosphoric triamide is accepted(see Tetrahedron Lett. 21, 3099 (1980)). The use of other solvents, forexample dimethylformamide, results in considerably lower yields of4-mercaptobiphenyl (for example 67% of theory—see Synthesis 9, 751(1983)).

The reaction of 4-bromobiphenyl with elemental sulphur and the cleavageof the reaction product with lithium aluminium hydride to give4-mercaptobiphenyl requires the use of lithium aluminium hydride, whichis difficult to handle (see Tetrahedron Lett. 13, 1283 (1972).

Also known are reduction processes for preparing 4-mercaptobiphenylstarting from aromatic sulphonyl chlorides and aromatic disulphides.However, reduction with hydrogen and noble metal catalysts requirestemperatures of up to 150° C. and pressures of up to 150 bar (see EP-A2755), and reduction with red phosphorus and iodine necessarily leads tophosphoric acid and hydrogen chloride being produced (see Chem. Ber. 99,375 (1966)) and requires red phosphorus, which is difficult to handle.

Finally, it is known that Bunte salts, i.e. salts of the type R-S-SO3M(R=organic radical, M=monovalent metal) in aqueous-acidic mediagenerally hydrolyse to give thiols (see Angew. Chem. 79, 525 (1967)).However, in the present case disulphides were produced.

DESCRIPTION OF THE INVENTION

We have now found S-(4-biphenyl)-thiosulfuric acids and salts thereofcorresponding to the formula (I)

in which

A represents hydrogen, an equivalent of a metal atom or optionallysubstituted ammonium and

R and R′ independently of one another each represent hydrogen,C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen.

In the formula (I),

A preferably represents hydrogen, sodium, potassium, ½ calcium, ½magnesium, ½ zinc, NH₄ or NH₄ substituted by 1 to 4 C₁-C₆-alkyl radicalsand

R and R′ independently of one another each represent hydrogen, methyl,ethyl, methoxy, ethoxy, fluorine or chlorine.

Particularly preferably, in the formula (I)

A represents hydrogen or sodium and

R and R′ represent hydrogen.

Furthermore, we have found a process for preparingS-(4-biphenyl)-thiosulfuric acids and salts thereof of the formula (I)which is characterized in that S-(4-biphenyl)-sulfinic acids or saltsthereof of the formula

in which

A, R and R′ are as defined in formula (I),

are reacted with an aqueous bisulfite solution at a pH in the range from2 to 7.

The preferred and particularly preferred meanings of A, R and R′ arealso stated in formula (II) as in formula (I).

Some of the S-(4-biphenyl)-sulfinic acids and salts thereof of theformula (II) required as starting materials are known and can beprepared in a known manner or analogously thereto (see Ann. Univ. MarieCurie-Sklodowska, Section Aa, Volume Date 1966, No. 21, 49 to 64 (1967).The compound of the formula (II) in question does not have to beemployed in pure form. It may, if appropriate, contain, for example, upto 25% by weight of the corresponding biphenylsulfonic acid and/or saltsthereof. The compound of the formula (II) in question is preferablyemployed in the form of its sodium salt.

Very particular preference is given to using the sodium salt ofS-(4-biphenyl)-sulfinic acid. Suitable aqueous bisulfite solutions are,in particular, aqueous alkali metal bisulphite solutions as areobtained, for example, when sulfur dioxide or sulfurous acid isintroduced in an aqueous sodium hydroxide solution or an aqueous sodiumcarbonate solution or when sodium disulfite (Na₂S₂O₅) is dissolved inwater. In addition to hydrogen sulfite ions, the aqueous bisulfiteSolution may additionally contain, for example, sulphite ions, sulfurousacid or dissolved sulfur dioxide. The aqueous bisulfite solution may,for example, be 10 to 50% by weight strength, and it is preferably 25 to45% by weight strength. Based on 1 mol of the compound of the formula(II) employed, it is possible to use, for example, an amount of aqueousbisulfite solution which corresponds to 1 to 5 mols of bisulfite. Thisamount is preferably from 1.5 to 3 mols.

If, after S-(4-biphenyl)-sulfinic acid or sulfinate of the formula (II)and aqueous bisulfite solution have been combined, the reaction mixturehas a pH outside the range of 2 to 7, it is necessary to bring the pHinto the range from 2 to 7, in the simplest case by addition of aqueoushydrochloric acid.

The reaction with the aqueous bisulfite solution is preferably carriedout at a pH of from 3 to 5 which can, if appropriate, be established byaddition of acid, for example by addition of aqueous hydrochloric acid.The more acidic the reaction and the longer the treatment in the moreacidic medium, the higher the risk that the reaction will not stop atthe stage of the S-(4-biphenyl)-thiosulfuric acids and salts thereof ofthe formula (II) but proceed to the formation of the correspondingbisdiphenyl disulfides of the formula (IV) (see further below). This maybe desired (see further below).

If appropriate, water, for example in an amount of up to 5, preferablyup to 3, parts by weight, based on one part by weight of the compound ofthe formula (II) used, may be added to the reaction with the aqueousbisulfite solution.

The reaction with the aqueous bisulfite solution can be carried out, forexample, at temperatures in the range from 50 to 200° C. Preference isgiven to 120 to 170° C. If the reaction is to be carried out attemperatures above the boiling point (at atmospheric pressure) of thereaction mixture, the use of closed and pressure-tight reactors isrequired. In such cases, pressures of up to 12 bar, for example, mayoccur.

After the reaction has ended, the resulting salt of theS-(4-biphenyl)-thiosulfuric acid can be separated off, for example, incrude form by cooling the reaction mixture, for example to roomtemperature, and filtering off and, if appropriate, drying theprecipitate which is then present. If desired, the product can bepurified further, for example by extraction with boiling ethanol.

From the resulting salt of a S-(4-biphenyl)-thiosulfuric acid, generallythe sodium salt, the corresponding S-(4-biphenyl)-thiosulfuric acid canbe liberated by methods known per se. Preferably, the correspondingthiosulfuric acid is liberated from the salt of such a thiosulfuric acidby reaction on an acidic ion exchanger.

From free S-(4-biphenyl)-thiosulfuric acids, any salts of the respectiveS-(4-biphenyl)-thiosulfuric acid can be prepared by neutralization withan appropriate base.

We have also found a process for preparing 4-mercaptobiphenyls of theformula (III)

in which

R and R′ are as defined in formula (I),

which is characterized in that S-(4-biphenyl)-thiosulfuric acids orsalts thereof corresponding to the formula (I) are heated in thepresence of a strong aqueous acid and the resulting bisdiphenyldisulfide of the formula

in which

R and R′ are as defined in formula (I), is reduced.

Suitable strong aqueous acids are, for example, sulphuric acid havingconcentrations of, for example, 0.05 to 30, preferably 1 to 30, % byweight. The amount of acid can be chosen such that, for example, a pHresulting in the reaction mixture is in the range from 0 to 2. Thetemperatures for the treatment with the strong aqueous acid can, forexample, be in the range from 50 to 200° C., preferably in the rangefrom 80 to 170° C.

From the reaction mixture, the bisdiphenyl disulfide prepared can beisolated by cooling the reaction mixture, for example to roomtemperature, and filtering off and, if appropriate, drying theprecipitate which is then present.

The reduction of the bisdiphenyl disulfide of the formula (IV) inquestion to the corresponding 4-mercaptobiphenyl of the formula (III)can, for example, be carried out according to known methods, such as byreduction with sodium borohydride (see DE-A 44 20 777) by catalyticreduction with molybdenum sulfide catalysts at high pressures (see J.Org. Chem. 24, 1598 (1959) of by catalytic reduction with palladiumcatalysts, Raney cobalt or Raney nickel at high pressures in a liquidtwo-phase system (see DE-A 17 68 421 and JP-A (Japanese PublishedSpecification) 60 199 871).

However, this reduction is preferably carried out as a catalyticreduction with metal catalysts of the 8th transition group of the PTE orwith catalysts of the Raney type in alcoholic solution and in thepresence of alkaline compounds, for example at temperatures in the rangefrom 20 to 200° C. and pressures of up to 50 bar. Such reductions formpart of the subject-matter of another patent application which wassubmitted simultaneously by the same applicant.

In the preparation according to the invention of 4-mercaptobiphenyls ofthe formula (III) from diphenyl sulfinic acids and salts thereof of theformula (11), it is not necessary to isolate theS-(4-biphenyl)-thiosulfuric acids and salts thereof of the formula (I)formed. It is possible, in the reaction with aqueous bisulfite solutionfor the formation of bisdiphenyl disulfides of the formula (IV), toestablish suitable pHs during or after the reaction and/or to usesufficiently long reaction times, and thus to proceed directly to thecorresponding bisdiphenyl disulfide of the formula (IV), withoutisolation of the S-(4-biphenyl)-thiosulfuric acids or salts thereof ofthe formula (I).

The bisdiphenyl disulfide of the formula (IV) in question does not haveto be used in pure form for the reduction, in particular when it is tobe carried out in the preferred manner described above. It is possible,for example, to mix the still moist filter cake obtained in thepreparation with alcohol, an alkaline compound and catalyst and then tocarry out the hydrogenation.

The S-(4-biphenyl)-sulfinic acids and salts thereof of the formula (II)which are required for the preparation according to the invention of4-mercaptobiphenyls of the formula (III) can also be prepared in situ byreacting a corresponding diphenyl-4-sulfonyl chloride of the formula

in which

R and R′ are as defined in formula (I),

at a pH in the range from 6 to 10 with aqueous bisulfite solution atfrom 40 to 80° C, followed by addition of SO₂ and heating to from 70 to180° C. The bisdiphenyl disulfides of the formula (IV) are obtaineddirectly, without intermediate isolation of the respectiveS-(4-biphenyl)-sulfinic acids or salts thereof of the formula (II) andwithout isolation of the respective S-(4-biphenyl)-thiosulfuric acids orsalts thereof of the formula (I).

In this procedure, the pH during the reaction with aqueous bisulfitesolution is preferably at from 7.5 to 9, and the temperature after theintroduction of SO₂ is preferably at from 90 to 160° C. If the reactionis carried out above the boiling point of the reaction mixture (atatmospheric pressure), closed and pressure-tight reaction vessels haveto be used.

The present invention provides a process for preparing4-mercaptobiphenyls of the formula (III) via the corresponding novelS-(4-biphenyl)-thiosulfuric acids or salts thereof of the formula (I)which has a number of advantages. Thus, no waste water containing heavymetals is produced, the 4-mercaptobiphenyls of the formula (III) areobtained in high yields, no particular precautions for handlingcarcinogenic solvents and no reagents which are difficult to handle arerequired, no coproducts are produced and it is possible to avoid highpressures. The sum of these positive effects is particularly surprisingsince Angew. Chem. 79, 525 (1967) describes the acidic hydrolysis ofBunte salts as a generally suitable method for producing thiols. This isnot so in the present case. Under the conditions described, thebisdiphenyl disulphides were formed here. These have to be cleavedreductively to give mercaptan. It is particularly surprising that, inspite of the many steps, biphenylsulfonyl chlorides can be converted bythis route via S-(4-biphenyl)-thiosulfuric acids in high yields into4-mercaptobiphenyl.

The invention is further described in the following illustrativeexamples in which all parts and percentages are by weight unlessotherwise indicated.

EXAMPLE Example 1

Preparation of a compound of the formula (I) from a compound of theformula (II)

140 g of diphenylsulfinic acid sodium salt (content 66.8% by weight, inaddition to 10.5% by weight of diphenylsulfonic acid sodium salt) werestirred into 200 ml of water with 210 ml of aqueous bisulfite solution(39% by weight strength). Using 37% by weight strength aqueoushydrochloric acid, the pH was adjusted to 4. This mixture was heated inan autoclave to 150° C. and then stirred at 150° C. and a pressurebetween 4.1 and 4.3 bar for 2 hours. After cooling to room temperature,the resulting suspension was filtered off with suction and the isolatedsolid was dried. This gave 126.4 g of crude S-(4-biphenyl)-thiosulfuricacid as sodium salt in a yield of 78% of theory. In addition tobiphenylsulfonic acid which had been entrained, unreacted sulfinic acid,but no bis-diphenyl disulfide, was detected as by-product by HPLC. Theisolated solid was extracted with boiling ethanol. On cooling of theextract, S-(4-biphenyl)-thiosulphuric acid sodium salt precipitated outas monohydrate. The isolated product had the IR absorption bandscharacteristic of Bunte salts. Elemental analysis gave the followingresults (calc./found): C 47.1/47.4; If 3.6/3.6; 0 20.9/20.0; S20.9/20.9; Na 7.5/8.0.

Example 2

Preparation of a compound of the formula (IV) from a compound of theformula (I)

100 ml of 10% by weight strength aqueous sulfuric acid were initiallycharged and heated to 100° C., and 17 g of the crude substance fromExample 1 were then added. After a short period of time, at a pH of 0, awhite solid precipitated out from the solution which initially was onlyslightly turbid. After 30 minutes of stirring at 100° C., the batch wascooled to room temperature and then filtered off with suction. Theisolated solid was dried at 50° C. 200 mbar, giving 8.2 g of bisdihenyldisulfide with a content of 86.3% by weight (HPLC).S-(4-biphenyl)-thiosulfuric acid was no longer detectable.

Example 3

Preparation of a compound of the formula (IV) from a compound of theformula (V)

440 ml of aqueous bisulfite solution (39% by weight strength) and 550 mlof water were initially charged with 125 ml of aqueous sodium hydroxidesolution (45% by weight strength) and admixed with 2.2 g oftriethylbenzylammonium chloride. The mixture was heated to 60° C. In thecourse of one hour, 289.5 g of diphenyl-4-sulfonyl chloride (96% byweight strength) were introduced, and the pH was simultaneouslymaintained at 8 by metered addition of 45% by weight strength aqueoussodium hydroxide Solution. pH control was also carried out during the 3hours of extra stirring time. In an enamel autoclave, the reactionmixture was then admixed with 80 ml of sulphur dioxide and heated at130° C. for 3 hours. The batch was stirred at 130° C. and a pressurebetween 4.4 and 6.9 bar for 6 hours. During this time, the stage of theS-(4-biphenyl)-thiosulfuric acid was passed through. The mixture wassubsequently cooled to room temperature and vented and the resultingsuspension was filtered off with suction. The filter cake was dried,giving 237.4 g of bisdiphenyl disulfide with a content of 78.3% byweight. This corresponds to a yield of 91.2% of theory.

Example 4

Preparation of a compound of the formula (III) from a compound of theformula (IV)

314 g of bisdiphenyl disulfide (obtained according to Example 3) were,as a moist filter cake, suspended in 1 1 of ethanol and admixed with 44g of sodium hydroxide and 24.7 g of sodium borohydride. The resultingmixture was stirred at 70° C. for 6 hours and the suspension obtainedwas then filtered off with suction at 70° C. The filter residue waswashed with 250 ml of ethanol. The filtrate and the washing liquid werecombined and adjusted to pH 1 using 900 ml of 7% by weight strengthaqueous hydrochloric acid. The precipitated product was filtered offwith suction, washed with 500 ml of water and dried. This gave 174.2 gof a white powder with a melting point of 111 to 113° C. Its4-mercaptobiphenyl content was 98.3% by weight (determinediodometrically). This corresponds to a yield of 83.6% of theory, basedon the diphenyl-4-sulfonyl chloride employed.

Example 5

Preparation of a compound of the formula (III) from a compound of theformula (IV)

270 g of bisdiphenyl disulfide were prepared as in Example 3 and, as amoist filter cake, suspended in 800 ml of ethanol and admixed with 44 gof sodium hydroxide and 5.5 g of Raney nickel. In an autoclave, themixture was heated to 80° C., and a hydrogen pressure of 10 bar was thenapplied. After 4 hours, the uptake of hydrogen had ended. The batch wascooled and vented. After filtration with suction at 60° C., the motherliquor was acidified with 840 ml of 5.4% by weight strength aqueoushydrochloric acid, and the product precipitated out. The product wasfiltered off with suction, washed with 250 nil of water and dried. Thisgave 178.8 g of a white powder with a melting point of 110 to 112° C.The content of 4-mercaptodiplienyl was 91.8% by weight (determinediodometrically). This corresponds to a yield of 80.1% of theory, basedon the diphenyl-4-sulfonyl chloride employed.

Although the present invention has been described in detail withreference to certain preferred versions thereof, other variations arepossible. Therefore, the spirit and scope of the appended claims shouldnot be limited to the description of the versions contained therein.

What is claimed is:
 1. S-(4-biphenyl)-thiosulfuric acids and saltsthereof corresponding to the formula

in which A represents hydrogen, an equivalent of a metal atom oroptionally substituted ammonium and R and R′ independently of oneanother each represent hydrogen, a C₁-C₆-alkyl group, a C₁-C₆-alkoxygroup or a halogen.
 2. Acids and salts of claim 1, wherein in formula(I) A represents hydrogen, sodium, potassium, ½ calcium, ½ magnesium, ½zinc, NH₄ or NH₄ in which the hydrogen atoms are substituted with 1 to 4C₁-C₆-alkyl radicals and R and R′ independently of one another representhydrogen, methyl, ethyl, methoxy, ethoxy, fluorine or chlorine.
 3. Aprocess for preparing S-(4-biphenyl)-thiosulfuric acids andcorresponding to the formula (I)

in which A represents hydrogen, an equivalent of a metal atom oroptionally substituted ammonium and R and R′ independently of oneanother each represent hydrogen, a C₁-C₆-alkyl group, a C₁-C₆-alkoxygroup or a halogen, the process comprising reacting A)S-(4-biphenyl)-sulfinic acids or salts thereof of the formula (II)

with B) an aqueous bisulfite solution at a pH in the range from 2 to 7.4. The process according to claim 3, wherein 1 to 5 mols of bisulfiteare employed per mole of the compound of the formula (II) and thereaction with the aqueous bisulfite solution is carried out attemperatures in the range from 50 to 200° C.
 5. A process for preparing4-mercaptobiphenyls of the formula (III)

in which R and R′ are independently of one another each representhydrogen, a C₁-C₆-alkyl group, a C₁-C₆-alkoxy group or a halogen; thecomprising the steps of heating A) S-(4-biphenyl)-thiosulfuric acids andsalts corresponding to the formula (I)

in which A represents hydrogen, an equivalent of a metal atom oroptionally substituted ammonium and R and R′ independently of oneanother each represent hydrogen, a C₁-C₆-alkyl group, a C₁-C₆-alkoxygroup or a halogen, with B) an aqueous bisulfite solution at a pH offrom 2 to 7 in the presence of a strong aqueous acid and C) reducing theresulting bisdiphenyl disulfide of the formula (IV)

wherein the compounds of formula (I) are prepared with a process thatcomprises the steps of (1) reacting S-(4-biphenyl)-sulfinic acids orsalts thereof of the formula (II)

with (2) an aqueous bisulfite solution at a pH in the range from 2 to 7.6. The process of claim 5, wherein the strong aqueous acid used is 0.05to 30% by weight strength aqueous sulfuric acid and a pH in the rangefrom 0 to 2 is maintained in the reaction mixtures.
 7. The process ofclaim 5, wherein the heating in the presence of a strong aqueous acid iscarried out to from 50 to 200° C.
 8. The process of claim 5, wherein thereduction is carried out using sodium borohydride or as a catalyticreduction using molybdenum sulphide catalysts, palladium catalysts,Raney cobalt or Raney nickel.
 9. The process of claim 5, wherein theS-(4-biphenyl)-thiosulfuric acids and the salts thereof of the formula(I) are not isolated.
 10. The process of claim 5, wherein theS-(4-biphenyl)-sulfinic acids and salts thereof of the formula (II)required are prepared in situ by reacting a correspondingdiphenyl-4-sulfonyl chloride of the formula (V)

in which R and R′ are independently of one another represent hydrogen,methyl, ethyl, methoxy, ethoxy, fluorine or chlorine, at a pH in therange from 6 to 10 with aqueous bisulphite solution at from 40 to 80° C,followed by addition of SO₂ and heating to from 70 to 180° C.